Process and intermediates for the synthesis of 8-[{1-(3,5-bis-(trifluoromethyl)phenyl)-ethoxy}-methyl]-8-phenyl-1,7-diaza-spiro[4.5]decan-2-one compounds

ABSTRACT

This application discloses a process to synthesize 8-({1-(3,5-Bis-(trifluoromethyl)phenyl)-ethoxy)-methyl]-8-pheny-1.7-diaza-spiro[4.5]decan-2-one comprising reacting a compound of the Formula 27a-sulfonate with zinc in the presence of acetic acid.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. patent application Ser. No.12/531,859, issued as U.S. Pat. No. 8,552,191 on Oct. 8, 2013, which isa national phase application under 35 U.S.C. §371 of Internationalapplication number PCT/US2008/003640, filed Mar. 20, 2008, which claimsthe priority of U.S. Provisional Application No. 60/919,666, filed Mar.22, 2007, each of which is incorporated herein by reference in itsentirety.

FIELD OF THE INVENTION

This application discloses a novel process for the preparation of8-[{1-(3,5-Bis-(trifluoromethyl)phenyl)-ethoxy}-methyl]-8-phenyl-1,7-diaza-spiro[4.5]decan-2-onecompounds, which have utility, for example, as NK-1 receptor antagonistcompounds, and intermediates useful in the synthesis thereof.

BACKGROUND OF THE INVENTION

Identification of any publication, patent, or patent application in thissection or any section of this application is not an admission that suchpublication is prior art to the present invention.

The preparation of diazaspirodecan-2-ones for example,8-[{1-(3,5-Bis-(trifluoromethyl)phenyl)-ethoxy}-methyl]-8-phenyl-1,7-diaza-spiro[4.5]decan-2-one,for example,(5S,8S)-8-[{(1R)-1-(3,5-Bis-(trifluoromethyl)phenyl)-ethoxy}-methyl]-8-phenyl-1,7-diazaspiro[4.5]decan-2-one(the compound of Formula I) has been described in U.S. Pat. No.7,049,320 (the '320 patent), issued May 23, 2006, the disclosure ofwhich is incorporated herein in its entirety by reference.

The compounds described in the '320 patent are classified as tachykinincompounds, and are antagonists of neuropeptide neurokinin-1 receptors(herein, “NK-1” receptor antagonists). Other NK₁ receptor antagonistsand their synthesis have been described, for example, those described inWu et al, Tetrahedron 56, 3043-3051 (2000); Rombouts et al, TetrahedronLetters 42, 7397-7399 (2001); and Rogiers et al, Tetrahedron 57,8971-8981 (2001) and in published international application no.WO05/100358, each of which are incorporated herein in their entirety byreference.

“NK-1” receptor antagonists have been shown to be useful therapeuticagents, for example, in the treatment of pain, inflammation, migraine,emesis (vomiting), and nociception. Among many compounds disclosed inthe above-mentioned '320 patent are several noveldiazaspirodecan-2-ones, including the compound of Formula I, which areuseful in the treatment of nausea and emesis associated withchemotherapy treatments (Chemotherapy-induced nausea and emesis, CINE).

The synthesis method for preparing the compound of Formula I describedin the '320 patent generally follows Scheme I in the provision of8-[{1-(3,5-Bis-(trifluoromethyl)phenyl)-ethoxy}-methyl]-8-phenyl-1,7-diaza-spiro[4.5]decan-2-onecompounds.

The process for the preparation of the compound of Formula I describedin the '320 patent is carried out in 18 individual steps fromcommercially available starting materials (see the '320 patent at col.43, line 55 to col. 45, line 20; col. 75, line 55 to col. 80, line 21;col. 90 lines 35 to 63; and col. 98, line 1 to col. 99, line 24). Inmany steps of the process described in the '320 patent, intermediatecompounds must be isolated or isolated and purified before use in asubsequent step, often utilizing column chromatography for this purpose.In general, the synthetic scheme described in the '320 patent consumes alarger than desirable percentage of starting and intermediate compoundsin the production of unwanted isomers.

OBJECTIVES AND SUMMARY OF THE INVENTION

In view of the foregoing, what is needed is a synthetic scheme for thepreparation of8-[{1-(3,5-Bis-(trifluoromethyl)phenyl)-ethoxy}-methyl]-8-phenyl-1,7-diaza-spiro[4.5]decan-2-onecompounds which has a reduced number of steps, improves the percentageof intermediate compounds which are converted to the desiredstereoisomer, and provides a reaction scheme affording practical scaleup to a batch size suitable for commercial scale preparation.

These and other objectives are advantageously provided by the presentinvention, which in one aspect is a process of making8-[{1-(3,5-Bis-(trifluoromethyl)phenyl)-ethoxy}-methyl]-8-phenyl-1,7-diaza-spiro[4.5]decan-2-onecompounds of Formula I in accordance with Scheme II.

the process comprising:

-   -   (a) reacting the protected enamine of Formula III with a        nitrating agent to form the corresponding protected        nitro-enamine and subsequently reducing the product to a        protected piperidine of Formula IV;    -   (b) deprotecting the protected piperidine of Formula IV from        step “a” by reacting it with hydrogen in the presence of a        palladium catalyst to form the compound of Formula V;    -   (c) alkylating the compound of Formula V by reacting it with a        Michael acceptor under Michael addition conditions with an        acrylate to form the compounds of Formulae 27a and 27b;    -   (d) selectively precipitating a sulfonate salt of the free base        compound of Formula 27a formed in alkylating Step “c” by        reacting the reaction mixture from Step “c”, containing the        compound of Formula 27a, with a sulfonic acid of the formula        R⁵—SO₃H to form the precipitate of Formula 27a-sulfonate;    -   (e) reducing and cyclizing the compound of Formula 27a-sulfonate        to form the lactam of Formula I; and    -   (f) optionally, precipitating a hydrochloride salt form of the        compound of Formula I by reacting the free-base compound of        Formula I with HCl.

One aspect of the present invention is the provision of a process forsynthesizing the lactam compound of Formula I, the process comprisingreducing and cyclizing the compound of the Formula 27a-sulfonate in aone-pot reaction. In some embodiments, it is preferred to carry out thereaction by treating the compound of Formula 27a-sulfonate with aceticacid in the presence of zinc metal. In some embodiments, preferably thecompound of Formula 27a is dissolved in concentrated acetic acid and thesolution is introduced into a zinc powder/acetic acid suspension.Without wanting to be bound by theory, it is believed that the reactionconditions provided by the zinc metal/acetic acid reaction environmentfirst reduce the nitro group to an amino-group and then form the lactamby acid-catalyzed displacement of the acyl portion of the ester group,thereby cyclizing the compound of Formula 27a and forming the lactam ofFormula I.

Another aspect of the present invention is the provision of compound ofFormula 27a from the compound of Formula V using a Michael additionreaction yielding at least about 60% of the compound of Formula 27abased on the amount of the compound of Formula V employed. In someembodiments it is preferred to select a basic alumina to carry out theMichael addition. In some embodiments it is preferred to select theacrylate used as a Michael acceptor from in step “c” from acrylateshaving the structure of the compound of Formula 28a:

wherein R¹ is a linear, branched, or cyclic alkyl having up to 6 carbonatoms, phenyl, 2-methoxy-ethyl, 2-(dimethylamino)ethyl, (L)-menthyl,(D)-menthyl, dimethylamide, (R)-benzyl-oxazolidinonamide,(S)-benzyl-oxazolidinonamide, isobornyl, cis-pinan-2-yl,isopinocampheyl, adamantylmethyl, 2-adamantyl, 1-adamantyl, and(−)-8-phenylmenthyl, more preferably R¹ is selected from methyl,(−)-8-phenylmenthyl, isobornyl, 1-adamantanyl, 2-adamantanyl, adamantanemethanyl, and (+)-isopinocamphenyl, more preferably R¹ is selected frommethyl and isobornyl. In some embodiments it is preferred to carry outthe Michael addition using basic alumina, more preferably a basicalumina with Brockman activity level IV. In some embodiments it ispreferred to carry out the Michael addition using an R¹-acrylate Michaelacceptor wherein “R¹” is selected from methyl- and -isobornyl, morepreferably R¹ is methyl.

In some embodiments, in Step “d”, precipitation step, it is preferred toemploy a sulfonic acid of the formula R⁵—SO3H or oxalic acid, forexample, methylsulfonic acid, to precipitate the sulfonate salt of thecompound of Formulae 27a-sulfonate. In some embodiments it is preferredto select R⁵ from, methyl, alkyl, benzyl, and p-tolyl, more preferablyR⁵ is methyl.

Other aspects and advantages of the invention will become apparent fromfollowing Detailed Description.

DETAILED DESCRIPTION OF THE INVENTION

Terms used in the general schemes herein, in the examples, andthroughout the specification, include the following abbreviations,together with their meaning, unless defined otherwise at the point oftheir use hereinafter: Me (methyl); Bu (butyl); t-Bu (tertiary butyl);Et (ethyl); Ac (acetyl); t-Boc or t-BOC (t-butoxycarbonyl); DMF(dimethylformamide); THF (tetrahydrofuran); DIPEA(diisopropylethylamine); MTBE (methyltertiarybutyl ether); RT (roomtemperature, generally 25° C.); TFA (trifluoroacetic acid); TEA(triethyl amine).

As used herein, the following terms, unless otherwise indicated, areunderstood to have the following meanings:

The term “substituted” means that one or more hydrogens on thedesignated atom or group of atoms in a structure is replaced with aselection from the indicated group, provided that the designated atom'snormal valency under the existing circumstances is not exceeded, andthat the substitution results in a stable compound. Combinations ofsubstituents and/or variables are indicated when such combinationsresult in stable compounds. By “stable compound” or “stable structure”is meant a compound that is sufficiently robust to survive isolation toa useful degree of purity from a reaction mixture, and formulation intoan efficacious therapeutic agent.

The term “optionally substituted” means optional substitution with thespecified groups, radicals or moieties.

“Patient” includes both humans and animals.

“Mammal” means humans and other mammalian animals.

“Alkyl” means an aliphatic hydrocarbon group which may be linearstraight or branched and comprising about 1 to about 10 carbon atoms inthe chain. Branched means that one or more lower alkyl groups such asmethyl, ethyl or propyl, are attached to a linear alkyl chain.Non-limiting examples of suitable alkyl groups include methyl, ethyl,n-propyl, isopropyl, n-butyl, t-butyl and n-pentyl.

“Alkenyl” means an aliphatic hydrocarbon group containing at least onecarbon-carbon double bond and which may be straight or branched andcomprising about 2 to about 10 carbon atoms in the chain. Branched meansthat one or more lower alkyl groups such as methyl, ethyl or propyl, areattached to a linear alkenyl chain. Non-limiting examples of suitablealkenyl groups include ethenyl, propenyl, n-butenyl, 3-methylbut-2-enyland n-pentenyl.

“Alkylene” means a difunctional group obtained by removal of anadditional hydrogen atom from an alkyl group, as “alkyl” is definedabove. Non-limiting examples of alkylene include methylene (i.e.,—CH₂—), ethylene (i.e., —CH₂—CH₂—) and branched chains, for example,—CH(CH₃)—CH₂—.

“Aryl” means an aromatic monocyclic or multicyclic ring systemcomprising about 6 to about 14 carbon atoms, preferably about 6 to about10 carbon atoms. The aryl group can be optionally substituted with oneor more “ring system substituents” which may be the same or different,and are as defined herein. Non-limiting examples of suitable aryl groupsinclude phenyl and naphthyl.

“Cycloalkyl” means a non-aromatic mono- or multicyclic ring systemcomprising about 3 to about 10 carbon atoms, preferably about 3 to about6 carbon atoms. Non-limiting examples of suitable monocyclic cycloalkylsinclude cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyland the like. Non-limiting examples of multicyclic cycloalkyls include,but are not limited to 1-decalin, norbornyl and cognitors, adamantyl andcognitors.

“Halo” means a halogen selected from fluoro, chloro, bromo, or iodogroups.

“Aminoalkyl” means an alkyl as defined above having at least onehydrogen atom on the alkyl moiety replaced by an amino functional (i.e.,—NH₂) group. Alkylamino means an amino functional group having one orboth hydrogens replaced by an alkyl functional group, as “alkyl” isdefined above.

With reference to the number of moieties (e.g., substituents, groups orrings) in a compound, unless otherwise defined, the phrases “one ormore” and “at least one” mean that there can be as many moieties aschemically permitted, and the determination of the maximum number ofsuch moieties is well within the knowledge of those skilled in the art.

A wavy line

appearing on a structure and joining a functional group to the structurein the position of a bond generally indicates a mixture of, or eitherof, the possible isomers, e.g., containing (R)- and (S)-stereochemistry.For example,

means containing either, or both of

A wavy line which terminates a bond indicates that the portion of thestructure depicted is attached to a larger structure at the indicatedbond, for example,

implies that the nitrogen of the substituted piperidyl group depicted isbonded to an undepicted structure on which it is a substituent.

Lines drawn into ring systems, for example the substituted aryl group:

indicates that a substituent (R¹) may replace a hydrogen atom of any ofthe ring carbons otherwise bonded to a hydrogen atom. Thus, asillustrated, R¹ can be bonded to any of carbon atoms 2, 4, 5, or 6, butnot 3, which is bonded to a methyl substituent, or 1, through which thesubstituted aryl group is bonded.

As well known in the art, a bond drawn from a particular atom wherein nomoiety is depicted at the terminal end of the bond indicates a methylgroup bound through that bond to the atom, unless stated otherwise. Forexample:

represents

However, sometimes in the examples herein, the CH₃ moiety is explicitlyincluded in a structure. As used herein, the use of either conventionfor depicting methyl groups is meant to be equivalent and theconventions are used herein interchangeably for convenience withoutintending to alter the meaning conventionally understood for eitherdepiction thereby.

The term “isolated” or “in isolated form” for a compound refers to thephysical state of said compound after being isolated from a process. Theterm “purified” or “in purified form” for a compound refers to thephysical state of said compound after being obtained from a purificationprocess or processes described herein or well known to the skilledartisan, in sufficient purity to be characterizable by standardanalytical techniques described herein or well known to the skilledartisan.

When any variable (e.g., aryl, heterocycle, R², etc.) occurs more thanone time in any constituent or in a formula, its definition on eachoccurrence is independent of its definition at every other occurrence.

As mentioned above, a process for preparing the compound of Formula Ifrom the compound of Formula IIIa via intermediate compound of FormulaIII is described in the '320 patent.

Preparation of the compound of Formula IIIa from commercially available(S)-α-phenylglycine is described by M. J. O'Donnel; Z. Fang; X. Ma; andJ. C. Huffman in “NEW METHODOLOGY FOR THE SYNTHESIS OF α, α-DIALKYLAMINOACIDS USING THE ‘SELF-REGENERATION OF STEREOCENTERS’ METHOD:α-ETHYL-α-PHENYLGLYCINE”, Heterocycles, Vol 46, 1997, pp 617 to 630,(see pages 618 through 619 therein), which is incorporated herein byreference in its entirety.

In the process described in the '320 patent for the preparation of thecompound of Formula I, the compound of Formula III is converted to thecompound of Formula IIIb (in two steps by oxidation of a correspondingalcohol intermediate). Compound IIIb is then converted in one step tothe compound of Formula 20 shown in Scheme I above. Accordingly, the'320 patent describes preparation of the compound of Formula I from thecompound of Formula III in 13 individual process steps.

The inventors have surprisingly found that the compound of Formula I canbe prepared, as shown in Scheme II, below, from the compound of FormulaIII in 4 process steps. Accordingly, the process of the presentinvention eliminates at least half of the number of steps employed inprevious preparation processes. Moreover, as will be described below,various of the steps of the present invention process provide improvedyield of intermediate compounds for an overall increase in the amount ofthe compound of Formula I provided from a given amount of the compoundof Formula III initially employed in the process. As shown in Scheme II,the compound of Formula III utilizes benzyl carbamate as a protectinggroup for the enamine nitrogen. It will be appreciated that otherprotecting groups may alternatively be employed and still be within thescope of the present invention.

Optionally, after Step “d”, the compound of Formula I can beprecipitated from the reaction mixture as a salt by treatment of thereaction mixture workup with an acid. Accordingly, in some embodimentsit is preferred to react the free-base compound of Formula I present inthe reaction workup with an acid, for example, HCl, to precipitate asalt form of the compound of Formula I, for example, a hydrochloridesalt form. Next, each step of the process of Scheme II will be describedin greater detail.Nitration Step

Step “a” of the process of the present invention, provision of thenitro-substituted intermediate compound of Formula IV from thecorresponding enamine compound of Formula III, can be carried out inaccordance with Scheme IIa, wherein the substrate is first nitrated andthen the double bond of the six-membered ring is reduced.

In general, nitration is carried out in a non-protic, low polaritysolvent, for example THF and DME using a nitrating reagent, for examplenitronium tetrafluoroborate (nitronium-TFB), optionally in the presenceof potassium phosphate tribasic. In some embodiments it is preferred torun the reaction without K₃PO₄ in the reaction mixture and therebyminimize impurities which may otherwise be formed when K₃PO₄ is presentin the reaction mixture. In some embodiments it is preferred to carryout the nitration using nitronium-TFB in DME (in which nitronium-TFB hasacceptable solubility). Nitration of the compound of Formula III usingnitronium-TFB in THF solvent is described in published internationalapplication no. WO05/100358 (the '358 publication), albeit not in thecourse of synthesizing the compound of Formula I (see the '358publication, page 66, step “a” of preparative Example 5). The '358publication is incorporated herein by reference in its entirety. Oncethe nitrated intermediate compound has been prepared, it may be used asprepared in the reaction workup directly in subsequent steps, oroptionally, isolated from the reaction workup prior to using insubsequent steps.

Following nitration, the nitrated compound is treated with a hydridereducing agent, for example lithium borohydride and sodium borohydride,to reduce the protected enamine double bond of the nitrated intermediateto yield the compound of Formula IV. In some embodiments using DME asthe solvent in which the compound of Formula III is nitrated, it ispreferred to strip off the reaction solvent by distillation and replaceit with THF prior to carrying out the reduction step. This provides thenitrated intermediate in a solvent suitable for carrying out thereduction with a metal hydride without the need to isolate the nitratedintermediate. In some embodiments, it is preferred to carry out thereduction using lithium borohydride in THF.

Although it is preferred to use the above-described method for thepreparation of the compound of Formula IV, it will be appreciated thatother means may be selected to prepare the compound of Formula IV foruse in the process of Scheme II and be within the scope of the presentinvention.

Step b—Deprotection

Step “b” of the present invention process, deprotection of thepiperidine nitrogen in the compound of Formula IV to yield the compoundof Formula V, can be carried out using metal-catalyzed hydrogenation orby treating the intermediate of Formula IV under acid conditions.Examples of suitable acid deprotection conditions include, but are notlimited to trifluoroacetic acid (TFA) and a mixture of HBr/acetic acid.It will be appreciated that other deprotection schemes may also beemployed, for example, iodotrimethylsilane (TMS-iodide) and deprotectionusing thiols. The inventors have surprisingly found that when TMS-iodideis employed, the byproduct benzyliodide can be efficiently trapped withtriphenylphoshine to suppress benzylamine formation with the piperidinenitrogen of the deprotected product. In some embodiments it is preferredto use hydrogen and a hydrogenation catalyst, for example, a palladiummetal catalyst, to mediate the deprotection reaction in Step “b”, morepreferably the catalyst employed is Pd supported on carbon black. Insome embodiments it is preferred to carry out deprotection in an alcoholsolvent, for example, methanol. In some embodiments, it is preferred towork up the previous reduction step by adding methanol and distillingoff the reaction solvent until suitably concentrated, and using thecrude concentrated methanol solution directly in the subsequentdeprotection reaction.

Step c—Alkylation

After the deprotection step “b”, the piperidine of Formula V is coupledto an acrylate under base-catalyzed Michael addition conditions. In someembodiments it is preferred to carry out the Michael addition in asolvent selected from n-hexane, MTBE, cyclohexane, toluene, methanol,dimethyl formamide (DMF), and THF. In some embodiments it is preferredfor the solvent to be n-hexane. In some embodiments, the reactionmixture from the deprotection step “b” is worked up by successiveadditions of toluene, followed by azeotropic distillation, and thensuccessive additions of n-hexane, followed by distillation maintainingthe still pot between 30° C. and 60° C. until distillation ceases, thus,the residual mixture will have the lowest possible volume at this stilltemperature. In some embodiments it is preferred to employ the resultingconcentrate directly in the Michael addition step which follows, Step“c”.

In some embodiments it is preferred to select a Michael acceptor fromcompounds having the structure of Formula 28a:

wherein “R¹” is selected from alkyl, cycloalkyl (includingmulticyclicalkyls), and aryl, more preferably “R¹” is selected frommethyl, t-butyl, phenyl, 2-methoxy-ethyl, 2-(dimethylamino)ethyl,(L)-menthyl, (D)-Menthyl, Dimethylamide, (R)-Benzyl-oxazolidinonamide,(S)-benzyl-oxazolidinonamide, isobornyl, cis-pinan-2-yl,isopinocampheyl, adamantylmethyl, 2-adamantyl, 1-adamantyl, and(−)-8-phenylmenthyl, more preferably R is selected from methyl,(−)-8-phenylmenthyl, isobornyl, 1-adamantanyl, 2-adamantanyl, adamantanemethanyl, and (+)-isopinocampheyl, more preferably R¹ is methyl.

In some embodiments it is preferred to carry out the Michael additionreaction in the presence of a base. In some embodiments the base isselected from: an organic base, for example, a homogeneous base, forexample triethylamine, and a heterogeneous base, for example, basicpolymer resin having amine functionality, for example Amberlyst A-21®from Rohm and Haas; and a heterogeneous, inorganic base, for example analuminum oxide (neutral or basic), a metal alkoxide (for example,Mg(OEt)₂, and magnesium oxide. In some embodiments it is preferred toemploy a basic aluminum oxide to catalyze the Michael addition reaction,more preferably, basic aluminum oxide having a Brockman activity of I,II, III, or IV, available as an article of commerce, more preferably abasic aluminum oxide having a Brockman activity of IV having a 5 wt. %to 10 wt. % water content.

Several metal oxides have been found useful for catalyzing the Michaeladdition reaction, for example, magnesium oxide (MgO) and aluminum oxide(alumina). It will be appreciated that the Michael addition reaction canresult in two different isomers being produced, shown in the reactionScheme C-IIa as the compounds of Structures 27a (S-isomer, desiredisomer) and 27b (R-isomer, an undesired isomer). Although the ratio ofthe isomers produced in the Michael addition reaction can be varied byaltering the reaction solvent, the steric demand of the Michaelacceptor, and other reaction conditions, the inventors have surprisinglyfound that the choice of base can greatly influence the ratio ofS-isomer to R-isomer produced in the addition reaction. The inventorshave surprisingly found that magnesium oxide base producesproportionately more of the R-isomer than the desired S-isomer.Additionally, the inventors have surprisingly found that the use ofbasic alumina as a base in the Michael addition reaction selectivelyproduces more of the desired S-isomer over the R-isomer. Moreover, theinventors have surprisingly found that selecting Bockman activity levelIV basic alumina as the base in the Michael reaction producessubstantially more of the S-isomer than R-isomer, for example, usingbasic alumina of activity level IV, the inventive process can produce areaction product with a ratio of S-isomer to R-isomer that exceeds 3:1(75% S-isomer) even when it is used in reactions employing a stericallyundemanding Michael acceptor, for example, methyl acrylate.

Moreover, the inventors have found that the inventive Michael additionreaction, when run with both a base providing maximum yield of thedesired isomer, and employing a sterically demanding Michael acceptor,provides a reaction product comprising in some embodiments from about84% to about 86% of the S-isomer, and in some embodiments up to about90% S-isomer. Suitable sterically demanding Michael acceptors are, forexample, compounds containing a bornyl structure and compoundscontaining an adamantly structure. Additional examples of suitablesterically demanding Michael acceptors include, but are not limited to,with reference to the structure of Compound 28a (above), compoundswherein the “R¹” group is selected from:

which are isobornyl, cis-pinan-2-yl, (+)-isopinocampheyl,adamantly-methyl, 2-adamantyl, 1-adamantyl, and (−)-8-phenylmenthylsubstituents, respectively.

In some embodiments, to maximize the amount of desirable “S-isomer”produced in the Michael addition reaction it is preferred to usen-hexane for the reaction solvent, select aluminum oxide (basic) havingBrockman activity level IV as the base catalyst, and useisobornylacrylate as a Michael acceptor (thus “R¹” is isobornyl-).

The inventive Michael addition reaction can be carried out using thecompound of Formula IV (the protected precursor to the compound ofFormula V, see for example, deprotection Step B, above) to provide anacylated product which, upon deprotection of that product in accordancewith deprotection Step “b”, yields the compounds of Formula 27a andFormula 27b. Accordingly, the compound of Formula I can be produced byreversing the order of deprotection step b and alkylation step c.However, the inventors have surprisingly found that when used in thealkylation Step “c”, the protected compound of Formula IV yields agreater proportion of the undesirable R-isomer compound of Formula 27brelative to the amount of desired S-isomer compound of Formula 27aformed in the inventive Michael addition reaction under substantiallythe same reaction conditions as were used for carrying out the inventiveMichael addition using the compound of Formula V (deprotected compound).Accordingly, to maximize the amount of the desired S-isomer compound ofFormula 27a provided by the inventive Michael addition in the alkylationstep, it is preferred to deprotect the compound of Formula IV first toform the compound of Formula V and then carry out the alkylation steprather than carry out the alkylation step on the compound of Formula IVand deprotect the product to provide the compound of Formula 27a.

In some embodiments, the product of the Michael addition is preferablyisolated as a solution of the product by filtering the reaction mixtureto remove solids and concentrating the solution under vacuum. In someembodiments, preferably the concentrated solution is then reacteddirectly with a sulfonic acid of the formula R⁵—SO₃H or oxalic acid,where R⁵ is selected from methyl, benzyl, and p-toluoyl groups, toprovide the ester compound of Formula 27a as a crystalline precipitatedsulfonate salt of Formula 27a-sulfonate, see Scheme C-IIb (where R⁵ is amethyl group, thus, the methylsulfonate salt is precipitated). It willbe appreciated that other salts, including other sulfonate salts, may beprecipitated without departing from the scope of the invention.

Although some amount of the unwanted “R” isomer is coprecipitated withthe desired isomers of Formula 27a (27b-sulfonate), the precipitation inaccordance with Scheme C-IIb provides a solid comprising substantiallythe compound of Formula 27a-sulfonate. In some embodiments precipitationusing Scheme C-IIb provides a precipitated material containing more thanabout 96% the compound of Formula 27a-sulfonate (S-isomer) with lessthan 4% of the undesirable compound of Formula 27b-sulfonate (unwantedR-isomer) precipitated.

With reference to Scheme C-IIb, in some embodiments it is preferred toprecipitate the methane sulfonate salt of the free-base compound as acrystalline material from the reaction mixture prepared above bytreating the reaction mixture in a suitable solvent (for example, MTBE,or a mixed solvent, for example, toluene and isopropanol) with an excessof methanesulfonic acid, and crystallizing the resulting methansulfonatesalt from the mixture, either by cooling, seeding the mixture, or acombination of the two. In some embodiments it is preferred to avoidusing an alcohol solvent to suppress ester exchange reactions in theproduct which could lead to the formation of unwanted impurities. Theprecipitate is preferably isolated by vacuum filtration for use in thesubsequent lactam formation step “d”.

Step d—Lactam Formation

Formation of the lactam of Formula I from the compound of Formula27a-sulfonate is carried out by treating the sulfonate salt formed inalkylation step “c” (containing substantially only the compound ofFormula 27a-sulfonate) with suitable reagents to effect reduction of thenitro-group with simultaneous, contemporaneous, or sequentialcyclization to form the lactam of Formula I. Without wanting to be boundby theory, it is believed that the reaction conditions provided byemploying zinc metal and acetic acid results in reduction of thenitro-group of the compound of Formula 27a-sulfonate to thecorresponding amine (however transiently) with formation of the lactamof Formula I by intermolecular acylation (using the ester group present)of the newly formed amine, thereby cyclizing the substituents to formthe lactam of Formula I. In some embodiments it is preferred to carryout the lactam forming step “d” by reacting the compound of Formula27a-sulfonate with zinc metal in the presence of acetic acid. In someembodiments it is preferred to dissolve the sulfonate salt from Step “c”in concentrated acetic acid and combine that solution with a suspensionof zinc powder in concentrated acetic acid to carry out thelactam-forming reaction.

After formation of the compound of Formula I, optionally, the compoundof Formula I is extracted from the reaction mixture into toluene, andthe toluene solution is treated with hydrochloric acid to precipitatethe hydrochloride salt of the compound of Formula I. In some embodimentsit is preferred to recrystallize the hydrochloride salt thusprecipitated from mixed ethanol/isopropanol solvent.

In some embodiments, Step d is carried out under conditions in which asubstantial portion of the compound of Formula Ia1 is formed.

When reactor conditions favor slow reduction of the nitro group, forexample, when low intensity agitation is used in the reactor, theintermediate formed during reduction of the nitro group has sufficientlifespan to participate in the ring closing reaction in accordance withScheme IIIa.

Accordingly, the formation of the compound of Formula Ia1 is increasedwhen closing proceeds faster than reduction during thenitro-reduction/lactam formation Step d of the process.

The inventors have surprisingly found that once formed, the Compound ofFormula Ia1 can be converted in good yields to the compound of Formula Iusing Raney nickel as a hydrogenation catalyst to reduce the compound,in accordance with Scheme IIIb shown below.

Accordingly, when preparation of the compound of Formula Ia1 is notdesired, the product can be converted to the compound of Formula I ingood yields by reducing the compound of Formula Ia1 using hydrogen andRaney nickel as a hydrogenation catalyst. When such a reaction isdesired, preferably the reaction is carried out at a temperature ofabout 50° C.

EXAMPLES

Unless otherwise specified, all reagents are articles of commerce,laboratory grade, and used as received. The following solvents andreagents may be referred to by their abbreviations in parenthesis:

-   tertiary-butoxycarbonyl: t-BOC-   tetrahydrofuran: THF-   Dimethylformamide: DMF-   methyl-tertiarybutyl ether: MTBE-   mole: mol.

Following are general and specific methods for the preparation ofcompounds having formula I, III, IIIb, IV, V, 27a and 27b describedabove. There follows non-limiting examples illustrative of the presentinvention but not limiting the present invention.

Example 1 Preparation of Compound IIIb: Benzyl(2S)-2-({(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}methyl)-5-nitro-2-phenyl-3,4-dihydropyridine-1(2H)-carboxylate

Into a vessel equipped with a stirring apparatus was placed1,2-dimethoxyethane (DME, 200 liters) at 20° C. to 25° C. Compound III(20.0 kg, 34.5 moles) was dissolved in the DME. The solution was thencooled and maintained at a temperature of −50° C. to −55° C. Nitroniumtetrafluoroborate (5.52 kg, 41.6 moles) was slowly added to the coldsolution in aliquots sized to maintain the batch temperature between−55° C. and −48° C. The reaction mixture was maintained at −50 to −55°C. until HPLC analysis of the reaction mixture indicated that less than2% of the amount of the compound of Formula III initially used remainedin the reaction mixture.

At the end of the reaction, sodium carbonate solution (12 Kg Na₂CO₃dissolved in 50 L water) was added while allowing the temperature of thereaction mixture to rise. The reaction mixture temperature wasmaintained at between −20° C. and 0° C. during the addition of thesodium carbonate solution. After approximately 50 L of sodium carbonatesolution had been added, the pH of the mixture was evaluated using pHpaper and found to be pH 5.5. Solid sodium carbonate was added until themixture had a pH of greater than pH 7.0 but not exceeding pH 10. Duringthe addition of sodium carbonate, the temperature of the mixture wasmaintained between −20° C. and 0° C. When the pH had been adjusted to avalue between pH 7.0 and pH 10, it was warmed to ambient temperature(between 20° C. and 25° C.). After warming, the reaction mixture wasfiltered and the filter cake washed with DME, which was combined withthe filtrate.

The filtrate was concentrated by distilling off the volatiles undervacuum 80 mbar to 150 mbar) to the lowest possible volume whilemaintaining the filtrate at a temperature between 30° C. and 50° C. Twoaliquots of MTBE (20 L each) were added to the concentrate in sequence.After each addition of MTBE to the concentrate, the mixture was againconcentrated by distilling under vacuum (from sufficient vacuum toinduce boiling up to 520 mbar) to the lowest possible volume whilemaintaining the filtrate at a temperature between 30° C. and 50° C.After the second distillation, MTBE (60 L) was added to the residue. Themixture was agitated, and permitted to settle, the layers of the mixturewere split. The organic layer was washed with water (3 aliquots of 20 Leach) and concentrated under vacuum (80 mbar to 200 mbar), to the lowestpossible volume while maintaining the organic layer at a temperaturebetween 30° C. and 50° C. THF was added to the concentrate (20 L), anddistilled off under vacuum (80 mbarr to 150 mbar) to achieve the lowestpossible volume while maintaining the mixture at a temperature between30° C. and 50° C. A second aliquot of THF was added to the concentrate(60 L) and the water content was determined by Karl Fischer titration tobe less than 0.2%. The solution thus obtained was analyzed by HPLC, andthe yield of the compound of Formula IIIb was determined to be 90%.

Example 2 Preparation of Compound IV: Benzyl(2S)-2-({(1R)-1-[3,5-bis(tri-fluoro-methyl)-phenyl]ethoxy}methyl)-5-nitro-2-phenylpiperidine-1-carboxylate

To the reaction mixture comprising the Compound IIIb solution (152.34kg, 53.3 kg active, 87.6 moles) produced in Example 1 was addedtetrahydrofuran (295 liters), and the mixture was cooled and maintainedat a temperature between −22° C. to −18° C. A solution of lithiumborohydride (7.92 kg, 10% in THF, 35.6 moles) was added to the mixtureat a rate permitting the mixture to be maintained at a temperaturebetween −22° C. and −18° C. The reaction was maintained at −22 to −18°C. until HPLC analysis indicated that the reaction was complete. At thecompletion of the reaction water (104 L) was added at a rate thatmaintained the temperature of the reaction mixture below 20° C.Concentrated hydrochloric acid was added to the mixture until the pH ofthe mixture was between pH 3.5 and pH 4.5. The mixture was concentratedat 30° C. to 50° C. under vacuum (80 mbar to 120 mbar) untildistillation of the solvent ceased. Additional methyl tart-butyl ether(86 L) was added to the concentrated reaction mixture and 43 L distilledoff at 30° C. to 50° C. under sufficient vacuum to maintaindistillation, reducing the THF level to less than 10 vol. %. MTBE (302L) was added into the concentrate. The mixture was agitated, then leftquiescent to settle. The layers were split, and the organic layer waswashed with 3 aliquots of water (42 L each aliquot).

After washing, the organic layer was concentrated at 30° C. to 55° C.under vacuum (80 mbar to 120 mbar) until distillation ceased. Methanol(130 L) was added to the concentrate. The mixture was heated to 30° C.to 50° C. under slight vacuum (80 mbar to 120 mbar) and 43 L of methanolwas distilled off. The solution thus obtained was evaluated by HPLC andfound to contain an amount of the compound of Formula IV equal to a 72%yield based on the amount of the compound of Formula III employed in thereaction.

Example 3 Preparation of Compound V:(2S)-2-({(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}methyl)-5-nitro-2-phenylpiperidine

The solution containing the compound of Formula IV prepared in theprevious step (53.8 kg, 18.8 kg active, 30.7 moles of Formula IV) wasdiluted with methanol (90 liters). Aqueous concentrated hydrochloricacid (5.1 liters) was slowly added to the agitated solution whilemaintaining the mixture at a temperature of between 20° C. to 30° C.Into a separate vessel containing palladium on charcoal catalyst (1.5kg, 10% on charcoal, 54% water) was slowly added Methanol (19 liters)while the mixture was slowly agitated to form a catalyst suspension.While continuing to slowly agitate the suspension, the solution ofcompound IV was slowly added to the suspension while maintaining themixture at a temperature of from 20° C. to 25° C. After all of thesolution of compound IV had been added, the mixture was placed under 1-3bar of hydrogen pressure and agitated vigorously while maintaining thereaction mixture at a temperature of between 20° C. and 25° C. until thereaction was complete as determined by HPLC. The reaction mixture wasfiltered through Dicalite® (0.5 kg) and the filter cake washed withmethanol, which was combined with the filtrate. The filtrate was placedunder vacuum (500 mbar) and concentrated while maintaining thetemperature of the filtrate between 20° C. and 30° C. until distillationceased. During the concentrating procedure, when the mixture wasconcentrated to about 20% of the initial volume, the mixture wasanalyzed by HPLC.

After the mixture had been concentrated, toluene (113 L) was added tothe concentrate. The pH of the residue was adjusted by addition ofsodium carbonate solution (7.8 Kg sodium carbonate dissolved in 79 L ofwater) to a value between pH 9 and pH 10. When the desired pH range hadbeen achieved, the mixture was settled and split. The organic layer waswashed with a sodium chloride solution (11.3 Kg sodium carbonatedissolved in 102 L of water) and concentrated under vacuum (80 mbar to120 mbar) while maintaining it at a temperature of 30° C. to 60° C.until distillation ceased. To the concentrate was added toluene (57 L)which was distilled off azetropically at 30° C. to 60° C. under vacuum.A second aliquot of toluene (57 L) was added and distilled offazetropically at 30° C. to 60° C. under vacuum. Karl Fischer titrationindicated that the concentrate contained less than 0.2% water.

To the concentrate was added 2 aliquots of n-hexane (57 L each). Each ofthe hexane aliquots was subsequently distilled off under vacuummaintaining the mixture at 30° C. to 60° C. until distillation ceased.The resulting solution was evaluated by HPLC and found to contain anamount of the compound of Formula V equal to a 93% yield based on theamount of compound IV initially used. This solution was used in thesubsequent step.

Example 4 Preparation of Compounds 27a and 27b: Methyl3-[(3R/S,6S)-6-({(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}methyl)-3-nitro-6-phenylpiperidin-3-yl]propanoate

Into a vessel was placed N-hexane (106 liters). With stirring, 135.8 Kgof basic aluminum oxide was added (Brockmann IV, water content 9-14%,Camag, used as received) to form a suspension. The solution containing29.2 kg (13.5 kg active, 28.4 moles) of the compound of Formula Vprepared in the previous step was added to the suspension while stirringwas continued and the mixture temperature was maintained at atemperature between 20° C. and 25° C. The equipment was rinsed withadditional hexane and agitation of the reaction mixture was continuedfor 20 to 30 minutes after all of the solution had been added to thesuspension. Into the reaction mixture was added 14.74 kg (171.2 moles)methyl acrylate maintaining the reaction mixture at a temperaturebetween 20° C. and 25° C. The equipment was rinsed with additionaln-hexane and the mixture was maintained at ambient temperature until thereaction was completed as determined by HPLC. At the end of thereaction, the reaction mixture was filtered and the filter cake waswashed with toluene. The combined filtrate and wash were concentrated byapplying a vacuum and maintaining the temperature of the filtratebetween 30° C. and 60° C. until the filtrate is concentrated to thesmallest volume that permits it to maintain a free-flowingcharacteristic. The concentrate was evaluated by HPLC and found tocontain an amount of the compounds of Formulae 27a and 27b equivalent toa yield of 71% based on the amount of the compound of Formula V usedinitially. In determining yield it was found that the product containedboth diastereomers in a 2:1 ratio of the compound of Formula 27a(S-diastereomer) to the compound of Formula 27b (R-diastereomer) and theyield of the desired S-diastereomer (compound 27a) was 48% based on theamount of compound V initially used. (solution yields). The solution wasused directly to prepare the methylsulfonate salt in the next step.

Example 5 Preparation of Sulfonate Salts of Compounds of Formula 27a/27b

To the solution containing compounds of the Formulae 27a and 27b freebase prepared in Step 5 (containing 22.78 kg of both diastereomers,including 15.6 kg (27.7 moles) of the S-isomer) was added 62 liters ofMTBE maintaining the temperature of the mixture at 20° C. to 25° C. Thesolution was passed through a fine filter and the filter was rinsed withMTBE. The clear filtrate thus obtained was concentrated to about 3× at30° C. to 55° C. under slight vacuum (500 mbar). The concentrate wasdiluted with toluene and the temperature of the mixture was adjusted to20° C. to 25° C. Methane sulfonic acid (2.0 Kg, 0.75 eq) was added tothe mixture over 20 to 30 minutes while maintaining the reaction mixtureat a temperature between 20° C. and 25° C. After acid addition thereaction mixture was agitated for 15 to 20 minutes. An additional 2.1 Kg(0.79 eq) of methanesulfonic acid was added to the suspension whilemaintaining the temperature and agitation. The reaction mixture wasagitated at 20° C. to 25° C. for an additional 50 to 60 minutesfollowing addition and then cooled to a temperature between 0° C. and 5°C., then agitated for an additional 50 to 60 minutes. At the end of theagitation period the reaction mixture was filtered, the wet cake waswashed with a 1:1 mixture of MTBE/toluene at 0° C. to 5° C. The filtercake (wet) was suspended in MTBE and agitated for 50 to 60 minutes whilemaintaining the suspension temperature at a temperature between 20° C.and 25° C. At the end of the agitation time, the suspension was cooledand maintained at a temperature between 0° C. and 5° C. and agitated foran additional 50 to 60 minutes.

The batch was filtered and washed with 0° C. to 5° C. MTBE. The wet cakewas maintained at a temperature of between 30° C. and 40° C. and driedunder vacuum (150 mbar to 200 mbar), and then for an additional 4 to 5hours at 45° C. to 50° C. under vacuum. The solids thus obtained wereevaluated by HPLC and found to contain an amount of the compound ofFormula 27a-sulfonate (S-isomer) equivalent to a yield of 88% based onthe amount of S-isomer initially present in the mixture. HPLC analysisindicated also that the salt precipitated had an isomeric ratio of 98%S-enationmer (27a-sulfonate, desired):2% R-enantiomer (27b-sulfonate,undesired). The solid thus obtained was used directly in the next step.

Example 6 Preparation of Formula I Compound Salt:(5S,8S)-8-({(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy}methyl)-8-phenyl-1,7-diazaspiro[4.5]decan-2-onehydrochloride monohydrate

Example 6A Preparation of the Compound of Formula I from 27a-sulfonate

A suspension was made by adding zinc powder (12.2 Kg, 186.6 moles) to 42liters of concentrated acetic acid with vigorous stirring. In a separatevessel was placed 4.04 Kg of the starting material prepared in Example5, above, and 4.1 Kg of a compound 27a-sulfonate compound prepared in asimilar reaction which yielded a salt comprising 88.2% S-enantiomer and7.8% R-enantiomer (total 8.14 kg of the sulfonate salts, about 95%S-enantiomer). The sulfonate salts were dissolved in 82 liters ofconcentrated acetic acid heated to 45° C. to obtain a solution. When allof the solids had dissolved the solution temperature was adjusted andmaintained at a temperature between 20° C. and 30° C. The solutioncontaining the compound of Formula 27a-sulfonate was added to thestirring zinc suspension while maintaining the mixture at a temperaturebelow 60° C. After all of the solution was added, the reaction mixturetemperature was adjusted and maintained at a temperature of from 55° C.to 60° C. until the reaction was complete, as determined by HPLC. At theend of the reaction the reaction mixture was then cooled and maintainedat a temperature of from 20° C. to 30° C.

The reaction mixture was filtered through Hyflo (4.12 kg) and the wetcake was washed with toluene. The wash was combined with the filtrateand the mixture was concentrated under vacuum (80 mbar to 120 mbar) bymaintaining the reaction mixture temperature between 30° C. and 60° C.until distillation ceased. To the concentrate was added 41 L of toluene.The resulting organic solution was washed successively with aliquots of2N hydrochloric acid solution (45 L), sodium carbonate solution (2aliquots of 82 L each, 8% solution) and sodium chloride solution (22 L,10% solution). The washed solution was filtered and the filter rinsedwith toluene which was combined with the filtrate. The filtrate wasseeded with seed crystals of the compound of Formula I maintaining thefiltrate at a temperature between 20° C. and 25° C. Concentratedhydrochloride acid was slowly added to the filtrate followed by finespirit (95:5 ethanol/isopropanol) maintaining the mixture at atemperature between 20° C. and 25° C. The mixture was agitated at 20° C.to 25° C. for 25 to 35 minutes and then cooled to 0° C. to 5° C. andagitated for 25 to 35 minutes. The mixture was filtered and the wet cakewashed with an aliquot of a 1:1 mixture of toluene/MTBE (10 L), followedby a second aliquot of MTBE (10 L) maintained at 20° C. to 25° C. Thewet cake was dried at 40° C. to 45° C. under vacuum. The yield of crudeCompound I was 88%.

The crude crystals of compound I (14.54 kg, 25.6 moles) wererecrystallized by dissolving the crude compound in a mixture of finespirit (35 liters; 95:5 ethanol/isopropanol), water with endotoxincontrol (35 liters) and hydrochloride acid (0.3 liter, 37%), and heatingthe solution to reflux with agitation. The refluxing solution was cooledand maintained at a temperature of between 74° C. to 77° C., andfiltered through a preheated pipe and in-line filter. The apparatus wasrinsed with a mixture of fine spirit (95:5 ethanol/isopropanol) andwater with endotoxin control maintained at 60° C. to 70° C. and combinedwith the filtrate. The temperature of the solution thus provided wasadjusted and maintained at a temperature between 72° C. and 74° C. andCompound I seed crystals were added. The seeded solution was maintainedat this temperature for 15 to 20 minutes and then cooled to atemperature between 0° C. and 5° C. at the rate of 0.5° C. per minute.The seeded solution was maintained at a temperature between 0° C. and 5°C. and agitated for 30 to 40 minutes. At the end of the time theresulting mixture was filtered and washed with a 40:60 mixture of finespirit (95:5 ethanol/isopropanol)/water with endotoxin control at 0° C.to 5° C. The wet cake was dried under vacuum (150 mbar to 200 mbar) at35° C. to 40° C. under vacuum. The yield of the compound of Formula Iwas determined by HPLC to be 97% based on the amount of the S-isomerpresent in the solids used initially.

A second run was carried out in accordance with the foregoing, however,at the end of the reaction period the reaction mixture was extractedwith aqueous sodium carbonate solution and the phases were split. Theorganic phase was added to dilute HCl to provide spontaneouscrystallization. In a subsequent run, when spontaneous crystallizationdid not occur, seed crystals were charged to seed crystal formation.Once crystalline product had precipitated, the product was filtered andthe cake washed successively with aliquots of water, a 1:1 mixture(vol.) of toluene:MTBE, and MTBE. The cake thus obtained was dried undervacuum at 40°-45° C. for approximately 8 h.

Example 6B Reduction of the Compound of Formula Ia1

Preparation of the compound of Formula I with co-production of asignificant amount of the compound of Formula Ia1 was carried out usingthe procedure described in Example 6 but starting with 47 Kg of thecompound of Formula 27a-sulfonate and utilizing an industrial scalereactor. The product of the reaction was found to contain 35 mole % ofthe compound of Formula I and 46 mole % of the compound of Formula Ia1.At the end of the reaction the reaction mixture was filtered throughHyflo (4.12 kg) and the wet cake was washed with toluene. The wash wascombined with the filtrate and the mixture was concentrated under vacuum(80 mbar to 120 mbar) by maintaining the reaction mixture at atemperature of less than about 60° C. until a residue which was capableof being stirred was obtained. The residue was azeotropically distilledwith denatured ethanol until distillation ceased then diluted with anadditional aliquot of ethyl alcohol. Into a separate reactor, withstirring, was charged Raney Nickel (ca. 25 kg) and ethanol denaturedwith toluene. The reactor was stirred for 20 min and the liquid decantedoff. The Raney Nickel was re-slurried with ethanol and the liquiddecanted until the moisture content of the residue was acceptable forrunning a hydrogenation reaction. When the moisture content wasacceptable, the reactor was charged with additional ethanol and thecatalyst was transferred to an autoclave with agitation as an ethanolslurry. The product mixture prepared as described above was added to theautoclave and the batch hydrogenated at 5 bar H₂ pressure at ca. 50° C.until a mixture of 81.5 mole % of the compound of Formula I and 1.9 mole% of the compound of Formula Ia1 was observed in the reaction mixture.The reaction mixture thus obtained was filtered and the resulting filtercake rinsed with ethanol and combined with the filtrate. The filtratewas concentrated under vacuum to a stirrable residue, azeotropicallydistilled with ethanol, and when distillation ceased, the residue wasdiluted with an additional aliquot of ethanol. A dilute solution ofaqueous HCl was added to the ethanol solution with stirring over 20minutes and the mixture was stirred for an additional 15 minutes. Theresulting reaction mixture was filtered, and the cake washedsuccessively with aliquots of water, a 1:1 mixture of MTBE:toluene, andMTBE. The washed cake was dried under vacuum at 40°-45° C. for about 8hours and sampled for residual solvent and water content. Thehydrogenation reaction over Raney nickel yielded about 60% of thecompound of Formula I based on the amount of compound of Formula Vemployed.

Example 7 Isomer Ratio Control by Varying Michael Addition ReactionConditions

The Michael addition reaction shown was carried out by dissolving aweighed amount of the compound of Formula V (reactions were run usingfrom about 200 mg to about 10 g of Formula V, depending upon theacrylate employed) into the solvent shown in the tables below. Thesolution was stirred at a selected temperature while addingapproximately 56 equivalents of Brockmann activity IV alumina obtainedfrom Aldrich or Camag (residual water content 7 wt. % to 12 wt. %, usedas received). After 10 minutes of additional stirring, 5 equivalents ofthe R-acrylate indicated in the tables below was added and stirring wasmaintained for 20 hours. At the end of the reaction time the reactionmixture was analyzed by HPLC for the combined amount of the compounds ofFormulae 27a and 27b and ratio of the compounds of Formulae 27a and 27bproduced in the reaction.

TABLE I Effects of: (i) Varying oxide catalyst; (ii) Running Michaeladdition in the presence or absence of a piperidine nitrogen protectinggroup; and (iii) Varying the “R” group of the acrylate. Isomer RatioIsomer Ratio Isomer Ratio Isomer Ratio (S:R) - Base = (S:R) - Base =(S:R) - Base = (S:R) - Base = “R” group of Brockman Activity I MgOBrockman Activity I MgO No. R¹-acrylate R² = H R² = H R² = Cbz R² = Cbz1 Methyl 63/37 20/80 2 (−)-8-Phenylmenthyl 78/22 25/75 15/85 3 Phenyl66/34 4 t-Butyl 69/31 34/66 30/70 25/75 5 Isobornyl 84/16 23/77 18/82 61-adamantanyl 69/31 7 2-adamantanyl 85/15 8 adamantane methanyl 86/14 9cis-Pinan-2-yl 66/34 10 (+)-Isopinocampheyl 73/27

The reactions run for Table I were carried out using a weight ofn-hexane 14× the weight of the acrylate employed in the reaction.Reactions were run at ambient temperature (about 20° C. to 25° C.). Thedata shown in Table 1 indicates that, for some acrylate acceptors, thepresence of a protecting group on the piperidine nitrogen can reversethe selectivity of the Michael addition reaction for the preferredisomer. It indicates also that basic alumina is the preferred basecatalyst for promoting formation of the preferred isomer, and thatselecting a sterically demanding acrylate, for example adamantanemethanyl-acrylate, promotes preferentially the formation of the desiredisomer.

TABLE II Effect of Solvent on Isomer Produced in the Michael AdditionStep Isomer Ratio Produced Run No. Solvent (S-isomer:R-isomer) 1n-Hexane 79:21 2 Toluene 84:16 3 Methanol 48:52 4 Dimethylformamide38:62 5 Tetrahydrofuran 51:49

The data in Table II were generated using the above-described additionreaction employing Brockman activity IV basic alumina and(−)-8-phenylmenthyl acrylate as the Michael acceptor with thedeprotected substrate compound of Formula V (thus “R²”═H). All runs wereconducted at ambient temperature (about 20° C. to 25° C.). These resultsindicate that non-polar solvents, for example n-hexane, or low polaritynon-protic solvents, for example toluene, promote formation of thedesired isomer.

TABLE III Influence of Alumina Activity Stage on Selection of PreferredIsomer Isomer Ratio Run No. Base (S-isomer:R-isomer 1 Neutral AluminaBrockman Activity I 63:37 2 Basic Alumina Brockman Activity I 51:49 3Basic Alumina Brockman Activity II 4 Basic Alumina Brockman Activity III5 Basic Alumina Brockman Activity IV 70:30

These reactions were run using methyl acrylate as the Michael acceptor,with a deprotected substrate (therefore “R*”═H) in n-hexane at 20° C. to25° C. The data in Table III indicates that the best selectivity for thedesired S-isomer is observed utilizing basic alumina having a Brockmanactivity level of IV. It was also found that conversion yields onBrockman activity I material were very low, typically 37% conversionafter reactions times comparable to those yielding complete conversionwith Brockman activity level IV alumina.

The above description of the invention is intended to be illustrativeand not limiting. Various changes or modifications in the embodimentsdescribed herein may occur to those skilled in the art. These changescan be made without departing from the scope or spirit of the invention

What is claimed is:
 1. A process for making compounds of Formula I

the process comprising: (a) reacting the protected enamine of FormulaIII, wherein R² is an enamine protecting group removable by catalytichydrogenation,

with a nitrating agent to form the corresponding protected nitro-enamineof Formula and subsequently reducing the product to a protectedpiperidine of Formula IV, wherein R² is as defined above;

(b) deprotecting the protected piperidine of Formula IV from step “a” byreacting it with hydrogen in the presence of a palladium catalyst toform the compound of Formula V,

(c) alkylating the compound of Formula V by reacting it under Michaeladdition conditions with an acrylate of the formula 28a,

to form the compounds of Formulae 27a and 27b,

(c) precipitating a sulfonate salt of Formula 27a-sulfonate by reactingthe compounds of Formula 27a and 27b formed in Step “c” with a sulfonicacid of the formula R⁵—SO₃H,

 and (d) forming the lactam of Formula I by treating the compound ofFormula 27a-sulfonate with acetic acid in the presence of zinc metal;wherein R⁵ is selected from benzyl, p-tolyl, and methyl and R¹ is alinear, branched, or cyclic alkyl having up to 6 carbon atoms, phenyl,2-methoxy-ethyl, 2-(dimethylamino)ethyl, (L)-menthyl, (D)-Menthyl,Dimethylamide, (R)-Benzyl -oxazolidinonamide,(S)-benzyl-oxazolidinonamide, isobornyl, cis-pinan-2-yl,isopinocamphenyl, adamantylmethyl, 2-adamantyl, 1-adamantyl, and(−)-8-phenylmenthyl.
 2. The process of claim 1 wherein R¹ is selectedfrom methyl, (−)-8-phenylmenthyl, isobornyl, 1-adamantyl, 2-adamantyl,adamantylmethyl, and (+)-isopinocamphenyl.
 3. The process of claim 1,wherein R² is Cbz.
 4. The process of claim 3, wherein R¹ is methyl.
 5. Acomposition comprising the mixture of the compounds of Formula I andFormula Ia1


6. A process for preparing the compound of Formula I from the compoundof Formula Ia1,

the process comprising reducing the compound of Formula Ia1 withhydrogen in the presence of Raney Nickel.
 7. A compound of the formula:

wherein R¹ is cyclic alkyl having up to 6 carbon atoms, phenyl,2-methoxy-ethyl, 2 (dimethylamino)ethyl, (L)-menthyl, (D)-menthyl,dimethylamide, (R) benzyl-oxazolidinonamide,(S)-benzyl-oxazolidinonamide, isobornyl, cis-pinan-2-yl,isopinocampheyl, adamantylmethyl, 2-adamantyl, 1-adamantyl, or (−)-8phenylmenthyl; or

wherein: R¹ is linear, branched or cyclic alkyl having up to 6 carbonatoms, phenyl, 2-methoxy-ethyl, 2-(dimethylamino)ethyl, (L)-menthyl,(D)-menthyl, dimethylamide, (R)-benzyl-oxazolidinonamide,(S)-benzyl-oxazolidinonamide, isobornyl, cis-pinan-2-yl,isopinocampheyl, adamantylmethyl, 2-adamantyl, 1-adamantyl, and(−)-8-phenylmenthyl; and R⁵ is selected from alkyl, benzyl, and p-tolyl.8. The compound of claim 7, wherein said compound is a compound of

wherein R⁵ is methyl.
 9. The process of claim 1, further comprising: (e)precipitating an hydrochloride salt form of the compound of Formula I byreacting the free-base compound of Formula I with HCl.